Abstract

M1 macrophage membrane coated nanoparticles exhibits significant radio-taxis activity. • Engineering the coating membrane to overexpress SIRPα enhances macrophage phagocytosis. • Radiotherapy and diABZI@PLGA@SIRPα-M1M synergistically inhibit local and distant tumors. • The nanoplatform synergizes with radiotherapy to potentiate systemic anti-tumor immunity. The combination of radiotherapy (RT) and immunotherapy holds great promise yet remains suboptimal in clinic due to inefficient drug accumulation and immunosuppressive tumor microenvironment. To address this, we developed a genetically engineered biomimetic nanomedicine (diABZI@PLGA@SIRPα-M1M) by coating STING agonist-loaded nanoparticles with membranes derived from M1 macrophages and engineered to overexpress SIRPα, the main receptor for CD47. This design leverages the inflammatory taxis of M1 macrophages, which allows the nanoparticles to be actively recruited to the RT site and achieve enhanced tumor-specific accumulation. Furthermore, the surface SIRPα protein efficiently blocks the CD47 “don't eat me” signal, potentiating phagocytosis and antigen presentation by macrophages. Utilizing the immunostimulatory effects of the released STING agonist, this nanoplatform robustly reprograms the immunosuppressive microenvironment and synergizes with radiotherapy to trigger potent systemic antitumor immunity, significantly inhibiting local and distant tumor growth in murine models. This work presents a novel radio-tactic nanomedicine that precisely target RT site and deliver immunomodulators for effective combinational tumor therapy. Download: Download high-res image (194KB) Download: Download full-size image